{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:03:22Z","timestamp":1760144602129,"version":"build-2065373602"},"reference-count":36,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,5,6]],"date-time":"2024-05-06T00:00:00Z","timestamp":1714953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Sharjah"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Hearing impairment, a rare inherited condition, is notably prevalent in populations with high rates of consanguinity. The most common form observed globally is autosomal recessive non-syndromic hearing loss. Despite its prevalence, this genetic disorder is characterized by a substantial genetic diversity, making diagnosis and screening challenging. The emergence of advanced next-generation sequencing (NGS) technologies has significantly advanced the discovery of genes and variants linked to various conditions, such as hearing loss. In this study, our objective was to identify the specific variant causing hearing loss in a family from Syria using clinical exome sequencing. The proband in the family exhibited profound deafness as shown by pure-tone audiometry results. The analysis of the different variants obtained by NGS revealed the presence of a nonsense mutation within the CLDN14 gene. Through Sanger sequencing, we verified that this variant segregates with the disease and was not present in the control population. Moreover, we conducted a comprehensive review of all reported deafness-related CLDN14 mutations and their associated phenotypes. Furthermore, we endeavored to carry out a comparative analysis between the CLDN14 and GJB2 genes, with the objective of identifying potential factors that could explain the notable discrepancy in mutation frequency between these two genes.<\/jats:p>","DOI":"10.3390\/genes15050588","type":"journal-article","created":{"date-parts":[[2024,5,6]],"date-time":"2024-05-06T15:05:01Z","timestamp":1715007901000},"page":"588","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Segregation of p.Arg68Ter-CLDN14 Mutation in a Syrian Deaf Family, Phenotypic Variations, and Comparative Analysis with the GJB2 Gene"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8039-3013","authenticated-orcid":false,"given":"Abdelaziz","family":"Tlili","sequence":"first","affiliation":[{"name":"Department of Applied Biology, College of Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates"},{"name":"Human Genetics and Stem Cell Laboratory, Research Institute of Sciences and Engineering, University of Sharjah, Sharjah 27272, United Arab Emirates"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5013-5155","authenticated-orcid":false,"given":"Abdullah Al","family":"Mutery","sequence":"additional","affiliation":[{"name":"Department of Applied Biology, College of Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates"},{"name":"Human Genetics and Stem Cell Laboratory, Research Institute of Sciences and Engineering, University of Sharjah, Sharjah 27272, United Arab Emirates"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jihen","family":"Chouchen","sequence":"additional","affiliation":[{"name":"Human Genetics and Stem Cell Laboratory, Research Institute of Sciences and Engineering, University of Sharjah, Sharjah 27272, United Arab Emirates"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/j.1749-6632.1991.tb19572.x","article-title":"Genetic epidemiology of hearing impairment","volume":"630","author":"Morton","year":"1991","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/S0140-6736(05)71047-3","article-title":"Sensorineural hearing loss in children","volume":"365","author":"Smith","year":"2005","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0092-8674(01)00200-8","article-title":"Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29","volume":"104","author":"Wilcox","year":"2001","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1086\/510022","article-title":"Tricellulin is a tight-junction protein necessary for hearing","volume":"79","author":"Riazuddin","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0378-5955(03)00338-1","article-title":"Expression patterns of claudins, tight junction adhesion molecules, in the inner ear","volume":"187","author":"Kitajiri","year":"2004","journal-title":"Hear Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1093\/hmg\/ddg210","article-title":"Claudin 14 knockout mice, a model for autosomal recessive deafness DFNB29, are deaf due to cochlear hair cell degeneration","volume":"12","author":"Belyantseva","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/jhg.2012.143","article-title":"Phenotypic variability of CLDN14 mutations causing DFNB29 hearing loss in the Pakistani population","volume":"58","author":"Bashir","year":"2013","journal-title":"J. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"331","DOI":"10.4103\/0971-6866.120828","article-title":"Genetic and molecular analysis of the CLDN14 gene in Moroccan family with non-syndromic hearing loss","volume":"19","author":"Charif","year":"2013","journal-title":"Indian J. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e2052","DOI":"10.1002\/mgg3.2052","article-title":"Mutation spectrum of non-syndromic hearing loss in the UAE, a retrospective cohort study and literature review","volume":"10","author":"Elsayed","year":"2022","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1002\/ajmg.a.34407","article-title":"Novel CLDN14 mutations in Pakistani families with autosomal recessive non-syndromic hearing loss","volume":"158A","author":"Lee","year":"2012","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1111\/ahg.12177","article-title":"Targeted Resequencing of Deafness Genes Reveals a Founder MYO15A Variant in Northeastern Brazil","volume":"80","author":"Manzoli","year":"2016","journal-title":"Ann. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.3389\/fgene.2019.01087","article-title":"A Novel Nonsense Mutation (c.414G>A; p.Trp138*) in CLDN14 Causes Hearing Loss in Yemeni Families: A Case Report","volume":"10","author":"Mohamed","year":"2019","journal-title":"Front. Genet."},{"key":"ref_13","first-page":"489","article-title":"Mutations in OTOF, CLDN14 & SLC26A4 genes as major causes of hearing impairment in Dhadkai village, Jammu & Kashmir, India","volume":"146","author":"Pandey","year":"2017","journal-title":"Indian J. Med. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s00439-016-1746-7","article-title":"A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect","volume":"136","author":"Pater","year":"2017","journal-title":"Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1002\/humu.20172","article-title":"Different mechanisms preclude mutant CLDN14 proteins from forming tight junctions in vitro","volume":"25","author":"Wattenhofer","year":"2005","journal-title":"Hum. Mutat."},{"doi-asserted-by":"crossref","unstructured":"Kitano, T., Kitajiri, S., Nishio, S., and Usami, S. (2019). Detailed Clinical Features of Deafness Caused by a Claudin-14 Variant. Int. J. Mol. Sci., 20.","key":"ref_16","DOI":"10.3390\/ijms20184579"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e1660","DOI":"10.1002\/mgg3.1660","article-title":"Targeted next-generation sequencing of deaf patients from Southwestern China","volume":"9","author":"Li","year":"2021","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/387080a0","article-title":"Connexin 26 mutations in hereditary non-syndromic sensorineural deafness","volume":"387","author":"Kelsell","year":"1997","journal-title":"Nature"},{"doi-asserted-by":"crossref","unstructured":"Beach, R., Abitbol, J.M., Allman, B.L., Esseltine, J.L., Shao, Q., and Laird, D.W. (2020). GJB2 Mutations Linked to Hearing Loss Exhibit Differential Trafficking and Functional Defects as Revealed in Cochlear-Relevant Cells. Front. Cell Dev. Biol., 8.","key":"ref_19","DOI":"10.3389\/fcell.2020.00215"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"202","DOI":"10.3389\/fncel.2015.00202","article-title":"Cellular and Deafness Mechanisms Underlying Connexin Mutation-Induced Hearing Loss\u2014A Common Hereditary Deafness","volume":"9","author":"Wingard","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1056\/NEJM199802193380813","article-title":"Connexin 26 R143W mutation associated with recessive nonsyndromic sensorineural deafness in Africa","volume":"338","author":"Brobby","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1093\/hmg\/6.9.1605","article-title":"Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans","volume":"6","author":"Zelante","year":"1997","journal-title":"Hum. Mol. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1086\/301807","article-title":"Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss","volume":"62","author":"Kelley","year":"1998","journal-title":"Am. J. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1097\/00001756-199906230-00010","article-title":"Three novel connexin26 gene mutations in autosomal recessive non-syndromic deafness","volume":"10","author":"Fuse","year":"1999","journal-title":"Neuroreport"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/j.ijporl.2007.01.010","article-title":"High prevalences of carriers of the 35delG mutation of connexin 26 in the Mediterranean area","volume":"71","author":"Lucotte","year":"2007","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4421","DOI":"10.1016\/j.sjbs.2021.04.036","article-title":"Whole exome sequencing, in silico and functional studies confirm the association of the GJB2 mutation p.Cys169Tyr with deafness and suggest a role for the TMEM59 gene in the hearing process","volume":"28","author":"Mahfood","year":"2021","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_27","first-page":"331","article-title":"Mutations of the Connexin 26 gene in families with non-syndromic hearing loss","volume":"4","author":"Moassass","year":"2011","journal-title":"Mol. Med. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.1017\/S001667231500004X","article-title":"Whole-exome sequencing and its impact in hereditary hearing loss","volume":"97","author":"Atik","year":"2015","journal-title":"Genet. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1515\/biol-2021-0134","article-title":"Association study of CLDN14 variations in patients with kidney stones","volume":"17","author":"Ullah","year":"2022","journal-title":"Open Life Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"107950","DOI":"10.1016\/j.heares.2020.107950","article-title":"Loss of inner hair cell ribbon synapses and auditory nerve fiber regression in Cldn14 knockout mice","volume":"391","author":"Schulze","year":"2020","journal-title":"Hear Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/j.1749-6632.2009.04057.x","article-title":"Structure and function of extracellular claudin domains","volume":"1165","author":"Krause","year":"2009","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_32","first-page":"335","article-title":"Cochlear nerve aplasia: Its importance in cochlear implantation","volume":"20","author":"Maxwell","year":"1999","journal-title":"Am. J. Otol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/j.tig.2020.10.003","article-title":"Hotspots of Human Mutation","volume":"37","author":"Nesta","year":"2021","journal-title":"Trends Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1101\/gad.1046203","article-title":"Early-replicating heterochromatin","volume":"17","author":"Kim","year":"2003","journal-title":"Genes Dev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1093\/genetics\/156.1.297","article-title":"Estimate of the mutation rate per nucleotide in humans","volume":"156","author":"Nachman","year":"2000","journal-title":"Genetics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1093\/nar\/gkaa1269","article-title":"Non-B DNA: A major contributor to small- and large-scale variation in nucleotide substitution frequencies across the genome","volume":"49","author":"Guiblet","year":"2021","journal-title":"Nucleic Acids Res."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/5\/588\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:40:10Z","timestamp":1760107210000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/5\/588"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,6]]},"references-count":36,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["genes15050588"],"URL":"https:\/\/doi.org\/10.3390\/genes15050588","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2024,5,6]]}}}